Understanding the Elusive Mechanism of Action of TCF7L2 in Metabolism

From the Division of Human Genetics and Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia,
Pennsylvania; and the Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Corresponding author: Struan F.A. Grant, grants{at}chop.edu.

Common intronic variation within the gene encoding transcription factor 7-like 2 (TCF7L2) is now considered to be definitively associated with type 2 diabetes (T2D). Since our first report of this association in
2006 (1), independent investigators have readily replicated this finding in all the main ethnic groups; in addition, from the first
genome-wide association study (GWAS) of T2D in Caucasians (2) onwards, the strongest association has been consistently with the TCF7L2 locus. Indeed, a meta-analysis of published studies worldwide as early as 2007 estimated a pooled odds ratio of 1.46 (with
an impressive P = 5.4 × 10−140) (3), making it one of the most statistically significant genetic findings in T2D to date.

Despite knowing that this association has been beyond doubt for over 6 years, the mechanism through which TCF7L2 exerts its effect on T2D is still very unclear, thus making the work by Kaminska et al. (4) in this current issue of Diabetes so timely.

TCF7L2 is a high-mobility group box-containing transcription factor and operates at the last key stage of the canonical Wnt
signaling transduction cascade, regulating the expression of a set of target genes. Moreover, tissue-specific isoforms have
been reported (5,6), with the transcript being heavily alternatively spliced at the 3′ terminus, …